한국발생생물학회지:발생과생식 (Development and Reproduction)

  • 제23권2호
  • /
  • Pages.79-92
  • /
  • 2019
  • /
  • 2465-9525(pISSN)
  • /
  • 2465-9541(eISSN)
한국발생생물학회 (The Korean Society of Developmental Biology)
권호 표지
DOI QR코드

DOI QR Code

T Lymphocyte Development and Activation in Humanized Mouse Model

  • 투고 : 2019.03.29
  • 심사 : 2019.04.28
  • 발행 : 2019.06.30
PDF 다운로드
⟨ 이전 논문 다음 논문 ⟩

초록

Humanized mice, containing engrafted human cells and tissues, are emerging as an important in vivo platform for studying human diseases. Since the development of Nod scid gamma (NSG) mice bearing mutations in the IL-2 receptor gamma chain, many investigators have used NSG mice engrafted with human hematopoietic stem cells (HSCs) to generate functional human immune systems in vivo, results in high efficacy of human cell engraftment. The development of NSG mice has allowed significant advances to be made in studies on several human diseases, including cancer and graft-versus-host-disease (GVHD), and in regenerative medicine. Based on the human HSC transplantation, organ transplantation including thymus and liver in the renal capsule has been performed. Also, immune reconstruction of cells, of the lymphoid as well as myeloid lineages, has been partly accomplished. However, crosstalk between pluripotent stem cell derived therapeutic cells with human leukocyte antigen (HLA) mis/matched types and immune CD3 T cells have not been fully addressed. To overcome this hurdle, human major histocompatibility complex (MHC) molecules, not mouse MHC molecules, are required to generate functional T cells in a humanized mouse model. Here, we briefly summarize characteristics of the humanized mouse model, focusing on development of CD3 T cells with MHC molecules. We also highlight the necessity of the humanized mouse model for the treatment of various human diseases.

키워드

참고문헌

  1. Abedi MR, Christensson B, Islam KB, Hammarstorm L, Smith CL (1992) Immunoglobulin production in severe combined immunodeficient (SCID) mice reconstituted with human peripheral blood mononuclear cells. Eur J Immunol 22:823-828. https://doi.org/10.1002/eji.1830220329
  2. Andre MC, Erbacher A, Gille C, Schmauke V, Goecke B, Hohberger A, Mang P, Wilhelm A, Mueller I, Herr W, Lang P, Handgretinger R, Hartwig UF (2010) Longterm human $CD34^{+}$ stem cell-engrafted nonobese diabetic/SCID/IL-2R $gamma^{null}$ mice show impaired $CD8^{+}$ T cell maintenance and a functional arrest of immature NK cells. J Immunol 185:2710-2720. https://doi.org/10.4049/jimmunol.1000583
  3. Billerbeck E, Horwitz JA, Labitt RN, Donovan BM, Vega K, Budell WC, Koo GC, Rice CM, Ploss A (2013) Characterization of human antiviral adaptive immune responses during hepatotropic virus infection in HLA-transgenic human immune system mice. J Immunol 191:1753-1764. https://doi.org/10.4049/jimmunol.1201518
  4. Brainard DM, Seung E, Frahm N, Cariappa A, Bailey CC, Hart WK, Shin HS, Brooks SF, Knight HL, Eichbaum Q, Yang YG, Sykes M, Walker BD, Freeman GJ, Pillai S, Westmoreland SV, Brander C, Luster AD, Tager AM (2009) Induction of robust cellular and humoral virusspecific adaptive immune responses in human immunodeficiency virus-infected humanized BLT mice. J Virol 83:7305-7021. https://doi.org/10.1128/JVI.02207-08
  5. Brugman MH, Wiekmeijer AS, van Eggermond M, van Eggermond M, Wolvers-Tettero I, Langerak AW, de Hass EF, Bystrykh LV, van Rood JJ, de Haan G, Fibbe WE, Staal FJ (2015) Development of a diverse human T-cell repertoire despite stringent restriction of hematopoietic clonality in the thymus. Proc Natl Acad Sci USA 112:E6020-6027. https://doi.org/10.1073/pnas.1519118112
  6. Bruno L, Fehling HJ, von Boehmer H (1996) The alpha beta T cell receptor can replace the gamma delta receptor in the development of gamma delta lineage cells. Immunity 5:343-352. https://doi.org/10.1016/S1074-7613(00)80260-5
  7. Cany J, van der Waart AB, Tordoir M, Franssen GM, Hangalapura BN, de Vries J, Boerman O, Schaap N, van der Voort R, Spanholtz J, Dolstra H (2013) Natural killer cells generated from cord blood hematopoietic progenitor cells efficiently target bone marrow-residing human leukemia cells in $NOD/SCID/IL2Rg^{null}$ mice. PLOS ONE 8:e64384. https://doi.org/10.1371/journal.pone.0064384
  8. Chan SH, Cosgrove D, Waltzinger C, Benoist C, Mathis D (1993) Another view of the selective model of thymocyte selection. Cell 73:225-236. https://doi.org/10.1016/0092-8674(93)90225-F
  9. Chung YS, Son JK, Choi B, Joo SY, Lee YS, Park JB, Moon H, Kim TJ, Kim SH, Hong S, Chang J, Kang MS, Kim SJ (2015) Co-transplantation of human fetal thymus, bone and $CD34(^{+})$ cells into young adult immunodeficient NOD/SCID $IL2Rgamma^{null}$ mice optimizes humanized mice that mount adaptive antibody responses. Clin Immunol 157:156-165. https://doi.org/10.1016/j.clim.2015.02.005
  10. Coleman CB, Lang J, Sweet LA, Smith NA, Freed BM, Pan Z, Haverkos B, Pelanda R, Rochford R (2018) Epstein-barr virus type 2 infects T cells and induces b cell lymphomagenesis in humanized mice. J Virol 92:e00813-18.
  11. Covassin L, Jangalwe S, Jouvet N, Laning J, Burzenski L, Shultz LD, Brehm MA (2013) Human immune system development and survival of non-obese diabetic (NOD)-scid IL2r$gamma^{null}$ (NSG) mice engrafted with human thymus and autologous haematopoietic stem cells. Clin Exp Immunol 174:372-388. https://doi.org/10.1111/cei.12180
  12. Danner R, Chaudhari SN, Rosenberger J, Surls J, Richie TL, Brumeanu TD, Casarea S (2011) Expression of HLA class II molecules in humanized NOD.Rag1KO.IL 2RgcKO mice is critical for development and function of human T and B cells. PLOS ONE 6:e19826. https://doi.org/10.1371/journal.pone.0019826
  13. Davis CB, Killeen N, Crooks ME, Raulet D, Littman DR (1993) Evidence for a stochastic mechanism in the differentiation of mature subsets of T lymphocytes. Cell 73:237-247. https://doi.org/10.1016/0092-8674(93)90226-G
  14. Dessureault S, Shpitz B, Alloo J, Rotstein O, Sandhu J, Hozumi N, Fernanders B, Gallinger S (1997) Physiologic human T-cell responses to OKT3 in the human peripheral blood lymphocyte-severe combined immunodeficiency mouse model. Transplantation 64:811-816. https://doi.org/10.1097/00007890-199709270-00004
  15. Deuse T, Hu X, Gravina A, Wang D, Tediashivili G, De C, Thayer WO, Wahl A, Garcia JV, Reichenspurner H, Davis MM, Lanier LL, Schrepfer S (2019) Hypoimmunogenic derivatives of induced pluripotent stem cells evade immune rejection in fully immunocompetent allogeneic recipients. Nat Biotechnol 37:252-258. https://doi.org/10.1038/s41587-019-0016-3
  16. Dudek TE, No DC, Seung E, Vrbanac VD, Fadda L, Bhoumik P, Boutwell CL, Power KA, Gladden AD, Battis L, Mellors EF, Tivey TR, Gao X, Altferd M, Luster AD, Tager AM, Allen TM (2012) Rapid evolution of HIV-1 to functional $CD8^{+}$ T cell responses in humanized BLT mice. Sci Transl Med 4:143ra98. https://doi.org/10.1126/scitranslmed.3003984
  17. Fayard E, Moncayo G, Hemmings BA, Hollander GA (2010) Phosphatidylinositol 3-kinase signaling in thymocytes: The need for stringent control. Sci Signal 3:re5. https://doi.org/10.1126/scisignal.3135re5
  18. Fehling HJ, Krotkova A, Saint-Ruf C, von Boehmer H (1995) Crucial role of the pre-T-cell receptor alpha gene in development of alpha beta but not gamma delta T cells. Nature 375:795-798. https://doi.org/10.1038/375795a0
  19. Fitzpatrick L, Makrigiannis AP, Kaiser M, Hoskin DW (1996) Anti-CD3-activated killer T cells: Interferongamma and interleukin-10 cross-regulate granzyme B expression and the induction of major histocompatibility complex-unrestricted cytotoxicity. J Interferon Cytokine Res 16:537-546. https://doi.org/10.1089/jir.1996.16.537
  20. Garcia S, Dadaglio G, Gougeon ML (1997) Limits of the human-PBL-SCID mice model: Severe restriction of the V beta T-cell repertoire of engrafted human T cells. Blood 89:329-336. https://doi.org/10.1182/blood.V89.1.329
  21. Gleichmann E, Pals ST, Rolink AG, Radaszkiewicz T, Gleichmann H (1984) Graft-versus-host reactions: Clues to the etiopathology of a spectrum of immunological diseases. Immunol Today 5:324-332. https://doi.org/10.1016/0167-5699(84)90126-9
  22. Halkias J, Melichar HJ, Taylor KT, Ross JO, Yen B, Cooper SB, Winoto A, Robey EA (2013) Opposing chemokine gradients control human thymocyte migration in situ. J Clin Invest 123:2131-2142. https://doi.org/10.1172/JCI67175
  23. Halkias J, Yen B, Taylor KT, Reinhartz O, Winoto A, Robey EA, Meichar HJ (2015) Conserved and divergent aspects of human T-cell development and migration in humanized mice. Immunol Cell Biol 93:716-726. https://doi.org/10.1038/icb.2015.38
  24. Henderson DA (1994) Role of the United States in the global response to emerging infections. J Infect Dis 170:284-285. https://doi.org/10.1093/infdis/170.2.284
  25. Hiramatsu H, Nishikomori R, Heike T, Ito M, Kobayashi K, Katamura K, Nakahata T (2003) Complete reconstitution of human lymphocytes from cord blood $CD34^{+}$ cells using the $NOD/SCID/gammac^{null}$ mice model. Blood 102:873-880. https://doi.org/10.1182/blood-2002-09-2755
  26. Hu Z, Xia J, Fan W, Wargo J, Yang YG (2016) Human melanoma immunotherapy using tumor antigen-specific T cells generated in humanized mice. Oncotarget 7:6448-6459. https://doi.org/10.18632/oncotarget.7044
  27. Huang M, Zhang W, Guo J, Wei X, Phiwpan K, Zhang J, Zhou X (2016) Improved transgenic mouse model for studying HLA class I antigen presentation. Sci Rep 6:33612. https://doi.org/10.1038/srep33612
  28. Ishikawa F, Yasukawa M, Lyons B, Yoshida S, Miyamoto T, Yoshimoto G, Watanabe T, Akashi K, Shultz LD, Harada M (2005) Development of functional human blood and immune systems in NOD/SCID/IL2 receptor ${\gamma}$ $chain^{null}$ mice. Blood 106:1565-1573. https://doi.org/10.1182/blood-2005-02-0516
  29. Ito M, Hiramatsu H, Kobayashi K, Suzue K, Kawahata M, Hioki K, Ueyama Y, Koyanagi Y, Sugamura K, Tsuji K, Heike T, Nakahata T (2002) $NOD/SCID/gamma(c)^{null}$ mouse: An excellent recipient mouse model for engraftment of human cells. Blood 100:3175-3182. https://doi.org/10.1182/blood-2001-12-0207
  30. Jaiswal S, Pazoles P, Woda M, Shultz LD, Greiner DL, Brehm MA, Mathew A (2012) Enhanced humoral and HLA-A2-restricted dengue virus-specific T-cell responses in humanized BLT NSG mice. Immunology 136:334-343. https://doi.org/10.1111/j.1365-2567.2012.03585.x
  31. Karpel ME, Boutwell CL, Allen TM (2015) BLT humanized mice as a small animal model of HIV infection. Curr Opin Virol 13:75-80. https://doi.org/10.1016/j.coviro.2015.05.002
  32. Klenerman P, Oxenius A (2016) T cell responses to cytomegalovirus. Nat Rev Immunol 16:367-377. https://doi.org/10.1038/nri.2016.38
  33. Kooreman NG, de Almeida PE, Stack JP, Nelakanti RV, Diecke S, Shao NY, Swijnenburg RJ, Sanchez-Freire V, Matsa E, Liu C, Connolly AJ, Hamming JF, Quax PHA, Brehm MA, Greiner DL, Shultz LD, Wu JC (2017) Alloimmune responses of humanized mice to human pluripotent stem cell therapeutics. Cell Rep 20:1978-1990. https://doi.org/10.1016/j.celrep.2017.08.003
  34. Kruse S, Buchler M, Uhl P, Sauter M, Scherer P, Lan TCT, Zottnick S, Klevenz A, Yang R, Rosl F, Mier W, Riemer AB (2018) Therapeutic vaccination using minimal HPV16 epitopes in a novel MHC-humanized murine HPV tumor model. Oncoimmunology 8:e1524694. https://doi.org/10.1080/2162402x.2018.1524694
  35. Lambolez F, Arcangeli ML, Joret AM, Pasqualetto V, Cordier C, Di Santo JP, Rocha B, Ezine S (2006) The thymus exports long-lived fully committed T cell precursors that can colonize primary lymphoid organs. Nat Immunol 7:76-82. https://doi.org/10.1038/ni1293
  36. Lan P, Tonomura N, Shimizu A, Wang S, Yang YG (2006) Reconstitution of a functional human immune system in immunodeficient mice through combined human fetal thymus/liver and $CD34^{+}$ cell transplantation. Blood 108:487-92. https://doi.org/10.1182/blood-2005-11-4388
  37. Lanzavecchia A, Sallusto F (2000) Dynamics of T lymphocyte responses: Intermediates, effectors, and memory cells. Science 290:92-97. https://doi.org/10.1126/science.290.5489.92
  38. Lapidot T, Pflumio F, Doedens M, Murdoch B, Williams DE, Dick JE (1992) Cytokine stimulation of multilineage hematopoiesis from immature human cells engrafted in SCID mice. Science 255:1137-1141. https://doi.org/10.1126/science.1372131
  39. Lavender KJ, Pang WW, Messer RJ, Duley AK, Race B, Phillips K, Scott D, Peterson KE, Chan CK, Dittmer U, Dudek T, Allen TM, Weissman IL, Hasenkrug KJ (2013) BLT-humanized C57BL/6 Rag2-/-gammac-/-CD47-/- mice are resistant to GVHD and develop Band T-cell immunity to HIV infection. Blood 122:4013-4020.
  40. Lee JY, Kim DC, Kim HJ (2015) Humanized (SCID) mice as a model to study human leukemia. Biomed Sci Lett 21:51-59. https://doi.org/10.15616/BSL.2015.21.2.51
  41. Lenschow DJ, Walunas TL, Bluestone JA (1996) CD28/B7 system of T cell costimulation. Annu Rev Immunol 14:233-258. https://doi.org/10.1146/annurev.immunol.14.1.233
  42. Li W, Kim MG, Gourley TS, McCarthy BP, Sant'Angelo DB, Chang CH (2005) An alternate pathway for CD4 T cell development: Thymocyte-expressed MHC class II selects a distinct T cell population. Immunity 23:375-386. https://doi.org/10.1016/j.immuni.2005.09.002
  43. Li Y, Masse-Ranson G, Garcia Z, Bruel T, Kok A, Strick-Marchand H, Jouvion G, Serafini N, Lim AL, Dusseaux M, Hieu T, Bourgade F, Toubert A, Finke D, Schwartz O, Bousso P, Mouquet H, Di Santo JP (2018) A human immune system mouse model with robust lymph node development. Nat Methods 15:623-630. https://doi.org/10.1038/s41592-018-0071-6
  44. Luce S, Guinoiseau S, Gadault A, Letourneur F, Blondeau B, Nitschke P, Pasmant E, Vidaud M, Lemonnier F, Boitard C (2018) Humanized mouse model to study type 1 diabetes. Diabetes 67:1816-1829. https://doi.org/10.2337/db18-0202
  45. Manz MG (2007) Human-hemato-lymphoid-system mice: Opportunities and challenges. Immunity 26:537-541. https://doi.org/10.1016/j.immuni.2007.05.001
  46. Masse-Ranson G, Dusseaux M, Fiquet O, Darche S, Boussand M, Li Y, Lopez-Lastra S, Legrand N, Corcuff E, Toubert A, Centlivre M, Bruel T, Spits H, Schwartz O, Levy Y, Strick-Marchand H, Di Santo JP (2019) Accelerated thymopoiesis and improved T-cell responses in HLA-A2/-DR2 transgenic BRGS-based human immune system mice. Eur J Immunol 49:954-965. https://doi.org/10.1002/eji.201848001
  47. McCune JM, Namikawa R, Kaneshima H, Shultz LD, Lieberman M, Weissman IL (1988) The SCID-hu mouse: Murine model for the analysis of human hematolymphoid differentiation and function. Science 241:1632-1639. https://doi.org/10.1126/science.2971269
  48. McCune JM, Peault B, Streeter PR, Rabin L (1991) Preclinical evaluation of human hematolymphoid function in the SCID-hu mouse. Immunol Rev 124:45-62. https://doi.org/10.1111/j.1600-065X.1991.tb00615.x
  49. Melkus MW, Estes JD, Padgett-Thomas A, Gatlin J, Denton PW, Othieno FA, Wega AK, Haase AT, Garcia JV (2006) Humanized mice mount specific adaptive and innate immune responses to EBV and TSST-1. Nat Med 12:1316-1322. https://doi.org/10.1038/nm1431
  50. Morton JJ, Bird G, Refaeli Y, Jimeno A (2016) Humanized mouse xenograft models: Narrowing the tumor-microenvironment gap. Cancer Res 76:6153-6158. https://doi.org/10.1158/0008-5472.CAN-16-1260
  51. Mosier DE, Gulizia RJ, Baird SM, Wilson DB (1988) Transfer of a functional human immune system to mice with severe combined immunodeficiency. Nature 335:256-259. https://doi.org/10.1038/335256a0
  52. Murphy KM, Reiner SL (2002) The lineage decisions of helper T cells. Nat Rev Immunol 2:933-944. https://doi.org/10.1038/nri954
  53. Najima Y, Tomizawa-Murasawa M, Saito Y, Watanabe T, Ono R, Ochi T, Suzuki N, Fujiwara H, Ohara O, Shultz LD, Yasukawa M, Ishikawa F (2016) Induction of WT1-specific human $CD8^{+}$ T cells from human HSCs in HLA class I Tg NOD/SCID/IL2rgKO mice. Blood 127:722-734. https://doi.org/10.1182/blood-2014-10-604777
  54. Niens M, Grier AE, Marron M, Kay TW, Greiner DL, Serreze DV (2011) Prevention of "Humanized" diabetogenic CD8 T-cell responses in HLA-transgenic NOD mice by a multipeptide coupled-cell approach. Diabetes 60:1229-1236. https://doi.org/10.2337/db10-1523
  55. Obenaus M, Leitao C, Leisegang M, Chen X, Gavvovidis I, van der Bruggen P, Uckert W, Schendel DJ, Blankenstein T (2015) Identification of human T-cell receptors with optimal affinity to cancer antigens using antigen-negative humanized mice. Nat Biotechnol 33:402-407. https://doi.org/10.1038/nbt.3147
  56. Peault B, Weissman IL, Baum C, McCune JM, Tsukamoto A (1991) Lymphoid reconstitution of the human fetal thymus in SCID mice with $CD34^{+}$ precursor cells. J Exp Med 174:1283-1286. https://doi.org/10.1084/jem.174.5.1283
  57. Prinz I, Sansoni A, Kissenpfennig A, Ardouin L, Malissen M, Malissen B (2006) Visualization of the earliest steps of gammadelta T cell development in the adult thymus. Nat Immunol 7:995-1003. https://doi.org/10.1038/ni1371
  58. Punt JA, Suzuki H, Granger LG, Sharrow SO, Singer A (1996) Lineage commitment in the thymus: Only the most differentiated (TCRhibcl-2hi) subset of $CD4^{+}CD8^{+}$ thymocytes has selectively terminated CD4 or CD8 synthesis. J Exp Med 184:2091-2099. https://doi.org/10.1084/jem.184.6.2091
  59. Ridge JP, Di Rosa F, Matzinger P (1998) A conditioned dendritic cell can be a temporal bridge between a CD4+ T-helper and a T-killer cell. Nature 393:474-478. https://doi.org/10.1038/30989
  60. Romero P, Zippelius A, Kurth I, Pittet MJ, Touvrey C, Iancu EM, Corthesy P, Devevre E, Speiser DE, Rufer N (2007) Four functionally distinct populations of human effector-memory $CD8^{+}$ T lymphocytes. J Immunol 178:4112-4119. https://doi.org/10.4049/jimmunol.178.7.4112
  61. Schoenberger SP, Toes RE, van der Voort EI, Offringa R, Melief CJ (1998) T-cell help for cytotoxic T lymphocytes is mediated by CD40-CD40L interactions. Nature 393:480-483. https://doi.org/10.1038/31002
  62. Serr I, Furst RW, Achenbach P, Scherm MG, Gokmen F, Haupt F, Sedlmeier EM, Knopff A, Shultz L, Willis RA, Ziegler AG, Daniel C (2016) Type 1 diabetes vaccine candidates promote human $Foxp3(^{+})Treg$ induction in humanized mice. Nat Commun 7:10991. https://doi.org/10.1038/ncomms10991
  63. Shultz LD, Brehm MA, Garcia-Martinez JV, Greiner DL (2012) Humanized mice for immune system investigation: Progress, promise and challenges. Nat Rev Immunol 12:786-798. https://doi.org/10.1038/nri3311
  64. Shultz LD, Lyons BL, Burzenski LM, Gott B, Chen X, Chaleff S, Kotb M, Gillies SD, King M, Mangada J, Greiner DL, Handgretinger R (2005) Human lymphoid and myeloid cell development in NOD/LtSz-scid IL2R $gamma^{null}$ mice engrafted with mobilized human hemopoietic stem cells. J Immunol 174:6477-6489. https://doi.org/10.4049/jimmunol.174.10.6477
  65. Shultz LD, Saito Y, Najima Y, Tanaka S, Ochi T, Tomizawa M, Doi T, Sone A, Suzuki N, Fujiwara H, Yasukawa M, Ishikawa F (2010) Generation of functional human T-cell subsets with HLA-restricted immune responses in HLA class I expressing NOD/SCID/IL2r $gamma^{null}$ humanized mice. Proc Natl Acad Sci USA 107:13022-13027. https://doi.org/10.1073/pnas.1000475107
  66. Shultz LD, Schweitzer PA, Christianson SW, Gott B, Schweitzer IB, Tennent B, McKenne S, Mobraaren L, Rajan TV, Greiner DL (1995) Multiple defects in innate and adaptive immunologic function in NOD/LtSz-scid mice. J Immunol 154:180-191.
  67. Smith DJ, Lin LJ, Moon H, Pham AT, Wang X, Liu S, Ji S, Rezek V, Shimizu S, Ruiz M, Lam J, Janzen DM, Memarzadeh S, Kohn DB, Zack JA, Kitchen SG, An DS, Yang L (2016) Propagating humanized blt mice for the study of human immunology and immunotherapy. Stem Cells Dev 25:1863-1873. https://doi.org/10.1089/scd.2016.0193
  68. Song J, Willinger T, Rongvaux A, Eynon EE, Stevens S, Manz MG, Flavell RA, Galan JE (2010) A mouse model for the human pathogen Salmonella typhi. Cell Host Microbe 8:369-376. https://doi.org/10.1016/j.chom.2010.09.003
  69. Steinman RM (1991) The dendritic cell system and its role in immunogenicity. Annu Rev Immunol 9:271-296. https://doi.org/10.1146/annurev.iy.09.040191.001415
  70. Strowig T, Gurer C, Ploss A, Liu YF, Arrey F, Sashihara J, Koo G, Rice CM, Young JW, Chadburn A, Cohen JI, Munz C (2009) Priming of protective T cell responses against virus-induced tumors in mice with human immune system components. J Exp Med 206:1423-1434. https://doi.org/10.1084/jem.20081720
  71. Suzuki M, Takahashi T, Katano I, Ito R, Ito M, Harigae H, Ishii N, Sugamura K (2012) Induction of human humoral immune responses in a novel HLA-DRexpressing transgenic $NOD/Shi-scid/{\gamma}c^{null}$ mouse. Int Immunol 24:243-252. https://doi.org/10.1093/intimm/dxs045
  72. Takahama Y (2006) Journey through the thymus: Stromal guides for T-cell development and selection. Nat Rev Immunol 6:127-135. https://doi.org/10.1038/nri1781
  73. Takaki T, Marron MP, Mathews CE, Guttmann ST, Bottino R, Trucco M, DiLorenzo TP, Serreze DV (2006) HLA-A*0201-restricted T cells from humanized NOD mice recognize autoantigens of potential clinical relevance to type 1 diabetes. J Immunol 176:3257-3265. https://doi.org/10.4049/jimmunol.176.5.3257
  74. Tary-Lehmann M, Saxon A (1992) Human mature T cells that are anergic in vivo prevail in SCID mice reconstituted with human peripheral blood. J Exp Med 175:503-516. https://doi.org/10.1084/jem.175.2.503
  75. Tary-Lehmann M, Saxon A, Lehmann PV (1995) The human immune system in hu-PBL-SCID mice. Immunol Today 16:529-533. https://doi.org/10.1016/0167-5699(95)80046-8
  76. Thomas S, Klobuch S, Sommer M, van Ewijk R, Theobald M, Meyer RG, Herr W (2014) Human $CD8^{+}$ memory and EBV-specific T cells show low alloreactivity in vitro and in $CD34^{+}$ stem cell-engrafted $NOD/SCID/IL-2R{\gamma}c^{null}$ mice. Exp Hematol 42:28-38. https://doi.org/10.1016/j.exphem.2013.09.013
  77. Traggiai E, Chicha L, Mazzucchelli L, Bronz L, Piffaretti JC, Lanzavecchia A, Manz MG (2004) Development of a human adaptive immune system in cord blood celltransplanted mice. Science 304:104-107. https://doi.org/10.1126/science.1093933
  78. Tsuchida M, Brown SA, Tutt LM, Tan J, Seehafer DL, Harris JP, Xun CQ, Thompson JS (1997) A model of human anti-T-cell monoclonal antibody therapy in SCID mice engrafted with human peripheral blood lymphocytes. Clin Transplant 11:522-528.
  79. Tuckett AZ, Thornton RH, O'Reilly RJ, van den Brink MRM, Zakrzewski JL (2017) Intrathymic injection of hematopoietic progenitor cells establishes functional T cell development in a mouse model of severe combined immunodeficiency. J Hematol Oncol 10:109. https://doi.org/10.1186/s13045-017-0478-z
  80. Velardi E, Tsai JJ, Holland AM, Wertheimer T, Yu VW, Zakrzewski JL, Tuckett AZ, Singer NV, West ML, Smith OM, Young LF, Kreines FM, Levy ER, Boyd RL, Scadden DT, Dudakov JA, van den Brink MR (2014) Sex steroid blockade enhances thymopoiesis by modulating Notch signaling. J Exp Med 211:2341-2349. https://doi.org/10.1084/jem.20131289
  81. Walsh NC, Kenney LL, Jangalwe S, Aryee KE, Greiner DL, Brehm MA, Shultz LD (2017) Humanized Mouse Models of Clinical Disease. Annu Rev Pathol 12:187-215. https://doi.org/10.1146/annurev-pathol-052016-100332
  82. Watanabe Y, Takahashi T, Okajima A, Shiokawa M, Ishii N, Katano I, Ito R, Ito M, Minegishi M, Minegishi N, Tsuchiya S, Sugamura K (2009) The analysis of the functions of human B and T cells in humanized $NOD/shi-scid/gammac^{null}$ (NOG) mice (hu-HSC NOG mice). Int Immunol 21:843-858. https://doi.org/10.1093/intimm/dxp050
  83. Wege AK, Melkus MW, Denton PW, Estes JD, Garcia JV (2008) Functional and phenotypic characterization of the humanized BLT mouse model. Curr Top Microbiol Immunol 324:149-65.
  84. Williams SS, Umemoto T, Kida H, Repasky EA, Bankert RB (1992) Engraftment of human peripheral blood leukocytes into severe combined immunodeficient mice results in the long term and dynamic production of human xenoreactive antibodies. J Immunol 149:2830-2836.
  85. Zakrzewski JL, Kochman AA, Lu SX, Terwey TH, Kim TD, Hubbard VM, Muriglan SJ, Suh D, Smith OM, Grubin J, Patel N, Chow A, Cabrera-Perez, Radhakrishnan R, Diab A, Perales MA, Rizzuto G, Menet E, Pamer EG, Heller G, Zuniga-Pflucker JC, Alpdogan O, van den Brink MR (2006) Adoptive transfer of T-cell precursors enhances T-cell reconstitution after allogeneic hematopoietic stem cell transplantation. Nat Med 12:1039-1047. https://doi.org/10.1038/nm1463